Friday, February 15, 2013

Let's Talk About Stem Cells!

by Ellen Mintz

It's early Friday morning, and still dark and cold, the time
of morning when only some animals are active and humans are all still
sleeping.I have my gear loaded in
the car, and am ready to get to work. I am not going out into the field to
catch kangaroo rats, catch fish, or track rattlesnakes (although those all
sound like fun projects!).My gear
is a pen, notebook, and collection of research abstracts, and I am headed down
to a meeting in the sunny beach town of La Jolla, CA, where some of the most
innovative and cutting edge research in stem cell biology is taking place at
research institutions like The Salk Institute, The Scripps Research Institute,
and UC San Diego.The amazing
applications of this research could improve the lives of many and result in hundreds
of applications in science and medicine.

The Salk Institute in La Jollahttp://www.galinsky.com/buildings/salk/

Stem Cell Basics

Stem
cells are unique cells located in special places around the body that can
differentiate into specialized cells or self renew and become more stem cells.They are influenced to change by their
environment, which includes other cells and factors released by those cells and
by the stem cells themselves.The
ultimate stem cells of the body, eggs and sperm, are referred to as totipotent,
meaning they can differentiate into any tissue type in the body.Pluripotent stem cells have the ability
to differentiate into any of the three tissue types in the body: mesoderm,
endoderm, or ectoderm.A neural
progenitor cell is an example of a multipotent stem cell; it has the ability to
differentiate into neurons or glial cells.Stem cells can also be unipotent, meaning they are the
direct precursors to a specific cell type.

The
gold standard of stem cells are human embryonic stem cells (ESCs), obtained
from the inner cell mass of a four day old blastocyst (post fertilization ball
of cells).These totipotent cells
can be induced to become any tissue type, and are easily obtained from IVF
clinics.However, some people have
ethical concerns over their use.In 2006, a method was developed to reprogram mature adult cells back
into a pluripotent state, similar to embryonic stem cells! This technique won
Shinya Yamanaka and Sir John Gurdon the Nobel Prize in Science and Medicine
this year, something that definitely has huge prospects for regenerative medicine,
cell therapies, and studying how different diseases develop.

Stem
cells are cultured, or grown, flat in dishes or allowed to form spheres,
mimicking the environment that they are naturally found in the body and
surrounded by growth and differentiation factors.These cells can then be used in cell therapies to treat many
different diseases and conditions, a really exciting prospect for regenerative
medicine! Let’s look at some of the diseases that have the potential to be
treated or cured eventually using stem cells.

Sir John Gurdon, 2012 Nobel Prize Winner

http://www.ox.ac.uk/media/news_stories/2012/121008.html

Shinya Yamanka, 2012 Nobel Prize Winner

http://gladstoneinstitutes.org/nobel/media.html

Parkinson’s Disease

Parkinson’s disease is a neurodegenerative disorder caused
by a loss of dopaminergic neurons (neurons that release dopamine as a
neurotransmitter) in the brain, in an area called the substantia nigra. It is one of the most common nervous
system disorders in the elderly, and exhibits symptoms such as muscle rigidity
and tremors, stooped posture, movement problems, and issues with balance and
walking.

The brain affected by PD

http://www.umm.edu/patiented/articles/what_parkinsons

_disease_what_causes_it_000051_1.htm

Current
treatments of Parkinson’s disease include administration of L-DOPA (the precursor
to dopamine), the implantation of fetal dopaminergic neurons into the brain, and
deep brain stimulation by electrical activity (see my last blog for more
information on this!).Unfortunately, these treatments only provide temporary relief of PD
symptoms, and fetal dopaminergic neurons are difficult to obtain and add a
whole other dimension of ethical issues with their use.

Cynomolgus Monkey

http://topics.time.com/thailand/pictures/

For
those of you who did not just take your Bio 502 oral exam, dopamine is created
in neurons when tyrosine (an amino acid) is converted to L-DOPA by the enzyme
tyrosine hydroxylase (TH), and is then acted upon again by the enzyme amino
acid decarboxylase to produce the final product.A common way to look for dopaminergic neurons in the brain
is to look for the presence of TH in neurons.

Takagi
et al. (2005) used primate ESCs and differentiated them into progenitors of
dopaminergic neurons, then treated them with factors that would allow them to
remain differentiated.These
neurons were then transplanted into cynomolgus monkeys that were treated with
1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (Try saying that five times fast!
We’ll just call it MPTP), which is used to induce PD in animal models.Following transplantation, these
neurons were still functional in their dopaminergic activity by releasing
dopamine, and were actually able to diminish PD symptoms in the monkeys!

Stained dopaminergic neurons from Takagi et al (2005)

Heart Attack and
Cardiac Function

In
2012, a clinical trial called CADUCEUS (full name: CArdiosphere-Derived
aUtologous stem Cells to reverse ventricular dysfunction) treated patients who
had suffered a myocardial infarction, or heart attack, with stem cells and
looked to see how it affected the damaged heart tissue.

Naming clinical trials

http://www.phdcomics.com/comics/archive.php?comicid=1100

A
heart attack is caused by a lack of oxygenated blood flow to the heart.Because there is no oxygen being
delivered to the tissue, the muscle tissue of the heart (the myocardium) cannot
pump like it should and begins to die.Despite treatment following a heart attack, patients often develop
scarring in place of healthy heart tissue, which results in reduced function,
further heart failure, or even death.Therapies aim to decrease this scarring, and instead rebuild the heart
with healthy tissue.While this
has been somewhat effective, the treatment does not always work equally well in
all cases, and does not always last as long as desired.

Damaged heart tissue following myocardial infarction

http://nursing-care-plan.blogspot.com/2011/12/

myocardial-infarction-pathophysiology.html

The
clinical trial resulted in an overall increase in viable, healthy heart tissue
when the patients were looked at collectively, and demonstrated that the
special stem cells that the researchers used (derived from a cardiosphere) were
able to not just reduce the amount of scar tissue but also stimulate the
regrowth of healthy myocardium.This is promising, but the next step would be to look at the function of
this tissue and the heart overall following a stem cell therapy.

Diabetes

Type
II Diabetes is a disease that is characterized by high blood glucose levels,
usually resulting from a resistance to insulin or a lack of insulin
production.Insulin is a hormone
produced by special cells (the islet cells) in the pancreas that causes an
uptake of glucose by tissues such fat, liver, and muscles.When cells do not respond to insulin,
glucose from the meal you just consumed continues to circulate in your blood,
leading to problems such as slowly healing infections, blurred vision, fatigue,
pain and numbness in the extremities, and eventual eye, kidney, and
cardiovascular disease.Family
history and genetic factors play a role in the development of Type II Diabetes,
and unhealthy lifestyle choices involving poor diet and lack of exercise only
exacerbate the problem.The best
cell therapy to treat Type II Diabetes is islet cell transplantation, however
there is a high cost associated with this as well as probable negative immune
reactions.

Human
mesenchymal stem cells are found most commonly in the bone marrow, but also in
certain fetal tissues like the umbilical cord, placenta, and fetal lung.Mesenchymal stem cells (MSCs) are cool
because they secrete important molecules that cause growth throughout the body,
and regulate the creation of blood cells (hematopoiesis), the creation of new
blood vessels (angiogenesis), and immune and inflammatory responses.As it turns out, MSCs have the ability
to differentiate into pancreatic islet cells!The placenta is an ideal place to obtain these cells because
it is usually discarded as a waste product following birth, it does not cause
as strong of an immune response in patients, and there is an extremely
decreased amount of ethical concern with its use.

Jiang
et al (2011) transplanted placental MSCs into ten patients with Type II
Diabetes who had insulin dysfunction and poorly controlled blood glucose
levels, as well as coronary artery disease, kidney disease, atherosclerosis,
and large limb neuropathy.The patients
received the transplant and continued to inject insulin as well, however this
was controlled for in the results by measuring the presence of c-peptide, a
molecule cleaved from the insulin precursor proinsulin to make insulin.There were no obvious negative side
effects to the transplantation, and C-peptide levels were significantly
elevated, meaning the islets were working and creating insulin!The MSCs were able to differentiate and
function as islet cells!

Stem
cell research is exciting, but there is still a lot of work left to do before
they are a viable treatment option for human use.Some challenges left to overcome include where we get the
stem cells from, how to differentiate them and keep them in that differentiated
state, and what factors affect how they behave.It is important to remember that animal models can only go
so far; inducing diseases in animals models only one aspect of a pathology that
may be caused by many complex factors. For example, the MPTP monkey models the cause
of PD, but does not experience the progressive degeneration that the disease
actually causes.There are also
ethical issues, especially pertaining to ESCs, and safety issues with
implanting stem cells into animals and their tendency to form tumors.Most stem cell clinical trials are able
to determine that the treatment is safe, but cannot make a determination about
the effectiveness at this time.The biology of stem cells and how they behave in the body as a whole is
a rapidly growing field, growing in leaps and bounds every year! New
discoveries are being made every day, with novel ideas for the use of stem
cells.

Keep
an ear out for stem cells in the news, and an eye on these blogs for more stem
cell biology from one of my CIRM Bridges program peers…

3 comments:

Thanks for the nice overview of some of the current aims of stem cell research Ellen! It's amazing that Cal Poly has this program and that all of you have the opportunity to go intern at some of the most cutting-edge facilities in the world! I'm exciting to see what research you get to participate in down the road!